Physical Properties and In Vivo Processing Native DPPIV is a ubiquitous type II transmembrane glycoprotein and a serine protease of the S9 prolyl-oligopeptidase family. In vivo, it is synthesized with a signal peptide which functions as the membrane anchoring domain.1,2 There is an 88% sequence homology between the human and porcine kidney enzymes. 3 Both the human and porcine kidney enzymes exist as homodimers with a subunit molecular weight of approx. 30 kDa. The high mannose 100 kDa DPPIV precursor is processed in the Golgi to yield a 124 kDa heavily N-and O-linked mature glycoprotein.4 It is then sorted to the apical membrane through the concerted action of both N- and O-linked glycans and it’s association with lipid microdomains.5 The porcine enzyme contains 18.3% carbohydrates, of which the glycan composition is 0.9% fucose, 3.4% mannose, 5.1% galactose, 8.2% glucosamine, and 0.7% sialic acid.1,2

Physiological Properties and Clinical Implications DPPIV is highly expressed on endothelial cells, epithelial cells and lymphocytes.8,9,10 It is also present in plasma in its soluble form.11

DPPIV is involved in the regulation of several important physiological processes: 12,13,14

Immune system

Inflamation

CNS

Endocrine functions

Bone marrow mobilization

Cancer growth

Cell adhesion

Glucose hemostasis

Sepsis/severe infection

Natural DPPIV substrates include: 12,13

Glucagon-like peptides-1 & 2

Glucose–dependent insulinotropic peptide

Neuropeptide Y

Substance P

Peptide YY

IGF-1

Prolactin

hCGα

Growth Hormone Releasing Factor

LHα

Thyrotropinα

Enkephalins

Vasostatin

Eotaxin

Interferon-γ inducible protein

IFN-inducible T-cell alpha-chemoattractant

Procalcitonin15

Macrophage-derived chemokine

Monokine induced by Interferon-γ

Natural DPPIV ligands include:12,16,17,18,19

Adenosine deaminase-I and II

Renal Na+/H+ ion exchanger NHE3 isoform

Fibronectin

DPPIV inhibitors have been found to improve glucose tolerance and preserve islet function in mice.20 DPPIV inhibitors were found to block entry of HIV-1 or HIV-2 into T lymphoblastoid and monocytoid cell lines.21

Specificity and Kinetics DPPIV has a post-proline dipeptidyl aminopeptidase activity that hydrolyzes N-terminal dipeptides from the unsubstituted N-terminus of peptides with the sequence of X-Pro-Z and X-Ala-Z.

The optimum pH for activity is 7.4-8.7.13,22 At pH 7.0 DPPIV exhibits about 45% of maximal activity and at pH 9.6 it exhibits about 90% of maximal activity. Below pH 5.0 the enzyme is essentially inactive.11,23

Sigma determines the enzymatic activity of DPPIV using the chromogenic substrate Gly-Pro-p-nitroanilde. Reported KM values are 0.66 mM for Gly-Pro-2-naphthylamide24 and 1 mM for Ala-Ala-2-naphthylamide.23